This FOA invites applications for projects that will: 1. generate
microbiome taxonomic, metagenomic and functional data from clinical
biospecimens obtained from a cohort(s) of carefully-phenotyped subjects with
a specific disease or health state; and 2. combine the microbiome and host
data to produce a community resource. This program is a component of the NIH
Common Fund Human Microbiome Project (http://commonfund.nih.gov/hmp/).

Key Dates

Posted Date

November 30, 2012

Letter of Intent Due Date(s)

January 8, 2013

Application Due Date(s)

February 8, 2013

AIDS Application Due Date(s)

Not Applicable

Scientific Merit Review

May/June, 2013

Advisory Council Review

August, 2013

Earliest Start Date

September, 2013

Expiration Date

February 9, 2013

Due Dates for E.O. 12372

Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in
the PHS 398
Application Guide except where instructed to do otherwise (in this FOA or
in a Notice from the NIH Guide
for Grants and Contracts). Conformance to all requirements (both in
the Application Guide and the FOA) is required and strictly enforced. While
some links are provided, applicants must read and follow all application
instructions in the Application Guide as well as any program-specific
instructions noted in Section IV. When
the program-specific instructions deviate from those in the Application Guide,
follow the program-specific instructions. Applications that do not
comply with these instructions may be delayed or not accepted for review.

Looking ahead: NIH is committed to transitioning all
grant programs to electronic submission using the SF424 Research and Related
(R&R) format and is currently investigating solutions that will accommodate
NIH’s multi-project programs. NIH will announce plans to transition the
remaining programs in the NIH
Guide to Grants and Contractsand on NIH’s Applying Electronically website.

This initiative is funded through the NIH Common Fund in the
NIH Office of the Director's Office of Strategic Coordination, which supports
cross-cutting programs that are expected to have exceptionally high impact. All
Common Fund initiatives invite investigators to develop bold, innovative, and
often risky approaches to address problems that may seem intractable or to
seize new opportunities that offer the potential for rapid progress.

The goal of this FOA is to generate exploratory dataset(s)
from microbiomes of well-phenotyped subjects in order to create a combined
dataset of microbiome and host properties as a community resource. The long-term
objective of this activity is for the community to be able to utilize this
combined dataset to explore whether study of the human microbiome beyond
sequenced-based analyses will yield important new insights in understanding
human health and disease. This FOA invites applications that propose to produce
taxonomic, metagenomic and functional human microbiome data – i.e., 'omic data:
microbiome transcriptomic, proteomic, and metabolomic data - from a human
cohort study of a specific health state or disease condition, and to create a
combined dataset of these data. Given the 3-year period of the initiative, it
is anticipated that the awardee(s) will not have sufficient time to completely
evaluate the dataset. However, applicants are asked to propose a
proof-of-principle test of the dataset in order to evaluate the useability of
the dataset for testing hypotheses about the role of the microbiome in health
and disease.

Background

The two goals of the first phase of the NIH Common Fund
Human Microbiome Project (HMP, http://www.commonfund.nih.gov/hmp,
2008-2012) were to determine whether study of the human microbiome at the
metagenomic level (1) would identify a core microbiome associated with specific
health or disease states and (2) correlates specific disruptions of the
microbiome with the presence of certain diseases. To study these questions the
HMP analyzed correlations between human health and/or specific diseases, and
the taxonomic and genetic composition of the microbiome. The preliminary
results from this phase demonstrated (1) that it is feasible to use
metagenomics as an approach to study the taxonomic and genetic composition of
the microbiome, and (2) that the taxonomic composition of an individual’s
microbiome (i.e., diversity and relative abundance of microbial members)
differs so significantly from the microbiome of another individual's with a
similar health status that taxonomic characterization alone, in some cases, may
not be sufficient to reveal correlations between the microbiome in specific
health conditions and disease states. Interestingly, in silico metabolic
pathway reconstructions of the metagenomic data from the HMP healthy cohort
study suggested that the microbiomes of healthy subjects may share similarities
in their metabolic pathways and that this may be indicative of a core property
of this health state. Further, in some of the HMP Demonstration Projects,
which were designed to evaluate the association of microbiomes with specific
diseases (http://www.hmpdacc.org/impacts_health/impact_health.php),
analysis of microbiome properties beyond metagenomics, such as of transcripts
or proteins or metabolites, suggested losses or gains of important microbiome
functions associated with some disease states. These new insights into
microbiome properties were not apparent from an analysis of the microbial
taxonomic composition alone. Additional information about the HMP and its
datasets and research products can be found at these websites (http://www.commonfund.nih.gov/hmp; http://www.hmpdacc.org).

Collectively, these studies suggest that it may be important
to consider microbiome functional properties when evaluating the role of the
microbiome in human health and disease. However, data are needed to enable
development of the necessary computational tools and analytic approaches to
study microbiome functional properties and to enable analysis of combined
datasets of microbiome and host properties. The long-term objective of this
program is to generate the necessary test data for the future development of
tools and analytic approaches to study the associations of microbiome functions
with host phenotypes. Once this type of working dataset is made available, tools
and analytic development can occur through either activities already underway
in the NIH Institutes/Centers (ICs) or may be supported through future IC-specific
program announcements or targeted FOAs.

Purpose

The purpose of this second phase of HMP is to create a
community resource that can be used to decipher the role of the microbiome in
human health through (1) acquisition of multi ‘omic types of data from a well-phenotyped
human cohort study(s), (2) defining practices for sample collection that
support multi-omic analyses, (3) making these data available to the broad
community through, as needed, appropriate controlled access databases for
qualified researchers, and (4) improving upon all of these methods and
protocols. These goals will be achieved by funding up to two exploratory
projects to generate and integrate a combined set of microbiome taxonomic,
metagenomic and functional property data with host phenotype data of samples
collected from human donors. The dataset will include multiple microbiome ‘omic
data types, including taxonomic composition and at least three of four other
‘omic data types, such as metagenomic, metatranscriptomic, metaproteomic and
metabolomic data. These data will be combined into one dataset and will be
rapidly released to the research community, as needed through controlled access
databases open to qualified researchers, so the community can participate in
the analysis of the combined dataset.

The requirements called for in this FOA are complex and it
is expected that applicants likely will need to form collaborations with other
groups that have the required bioinformatics expertise, the clinical
biospecimens or the ability to consent subjects to obtain the appropriate
biospecimens and the clinical data as well as the analytical facilities. The
partners in such a HMP Collaborative Center should have the necessary
capabilities to complete the sample and data gathering, data integration and
data deposition in the three-year project period. Because of the 3-year time line
of this initiative, the facility(ies) which will produce the data to measure
the proposed microbiome properties will need to be ready to embark on the
project with little or no scale up time.

Section II. Award Information

Funding Instrument

Cooperative Agreement: A support mechanism used when there
will be substantial Federal scientific or programmatic involvement.
Substantial involvement means that, after award, NIH staff will assist,
guide, coordinate, or participate in project activities.

Application Types Allowed

New

The OER
Glossary and the PHS 398 Application Guide provide details on these application
types.

Funds Available and Anticipated Number of Awards

The NIH Division of Program Coordination, Planning and
Strategic Initiatives, Office of Strategic Coordination intends to fund 1 or
2 awards, committing a total of up to $5,000,000 in FY 2013.

Award Budget

Applications may request up to $3.0 million per year
(total costs).

Award Project Period

Applications may request a project period of up to 3
years.

NIH grants policies as
described in the NIH Grants
Policy Statement will apply to the applications
submitted and awards made in response to this FOA.

Section III. Eligibility
Information

1. Eligible Applicants

Eligible Organizations

Higher Education Institutions

Public/State Controlled Institutions of Higher Education

Private Institutions of Higher Education

The following types of Higher Education Institutions
are always encouraged to apply for NIH support as Public or Private
Institutions of Higher Education:

Non-domestic (non-U.S.) Entities (Foreign Institutions) are
not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.
Foreign components, as defined in
the NIH Grants Policy Statement, are allowed.

Required Registrations

Applicant organizations must complete the following registrations
as described in the PHS 398 Application Guide to be eligible to apply for or
receive an award. Applicants must have a valid Dun and Bradstreet Universal
Numbering System (DUNS) number in order to begin each of the following
registrations.

System for
Award Management (SAM)– must maintain an active entity registration
(formerly CCR registration), to be renewed at least annually. Use the Sam.gov
“Manage Entity” function to manage your entity registrations. See the Grants
Registration User Guide at SAM.gov for additional information.

All Program Directors/Principal Investigators (PD(s)/PI(s))
must also work with their institutional officials to register with the eRA
Commons or ensure their existing eRA Commons account is affiliated with the eRA
Commons account of the applicant organization.

All registrations must be completed by the application due
date. Applicant organizations are strongly encouraged to start the registration
process at least6 weeks prior to the application due date.

Eligible Individuals (Program Director/Principal
Investigator)

Any individual(s) with the skills, knowledge, and resources
necessary to carry out the proposed research as the Program Director(s)/Principal
Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to
develop an application for support. Individuals from underrepresented racial
and ethnic groups as well as individuals with disabilities are always
encouraged to apply for NIH support.

Applicant organizations may submit more than one application,
provided that each application is scientifically distinct.

NIH will not accept any application that is essentially the
same as one already reviewed within the past thirty-seven months (as described
in the NIH
Grants Policy Statement), except for submission:

To an RFA of an application that was submitted previously as an
investigator-initiated application but not paid;

Of an investigator-initiated application that was originally
submitted to an RFA but not paid; or

Of an application with a changed grant activity code.

Section IV. Application and Submission Information

1. Address to Request
Application Package

Applicants are required to prepare applications according to
the current PHS 398 application forms in accordance with the PHS 398
Application Guide.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in
the PHS 398
Application Guide, except where instructed in this funding opportunity
announcement to do otherwise. Conformance to the requirements in the
Application Guide is required and strictly enforced. Applications that are out
of compliance with these instructions may be delayed or not accepted for review.

Letter of Intent

Although a letter of intent is not required, is not binding,
and does not enter into the review of a subsequent application, the information
that it contains allows IC staff to estimate the potential review workload and
plan the review.

By the date listed in Part 1. Overview
Information, prospective applicants are asked to submit a letter of intent
that includes the following information:

Applications must be prepared using the PHS 398 research
grant application forms and instructions for preparing a research grant
application. Submit a signed, typewritten original of the application,
including the checklist, and three signed photocopies in one package to:

All page limitations described in the PHS 398 Application
Guide and the Table of
Page Limits must be followed, with the following exception or additional
requirement:

The Research Strategy is limited to 30 pages.

General
Instructions

The applicant can select any type of Center structure that
will best address the goals of the FOA. It is expected that the HMP
Collaborative Center will include a variety of Components, such as
administrative, data coordinating and computational/bioinformatics/statistical
cores, clinical sites and/or analytical laboratories (genomics, proteomics,
metabolomics, etc.). Regardless of the proposed structure, the applicant must
present a clear organization of the different Components and a rationale for
this structure.

All instructions in the PHS 398 Application Guide must be
followed, with the following additional instructions:

PHS 398 Form Page 1

Face page for the Center; name of the PD/PI for the Center;
Multiple PD/PIs may be proposed.

PHS 398 Form Page 2

Provide a succinct description of the Center, addressing the
key aspects of the scientific scope and administrative structure.

Project/Performance
Sites. List the performance sites where the research will be
conducted.

Senior/Key
Personnel. List the PD/PI of the Center, followed by the
leaders of the key components and then other key personnel and then other
significant contributors.

Do not repeat biosketches if an individual has multiple
roles. Potential members of any Advisory or Steering Committees must not be
contacted or named in the application. However, the expertise required for these
positions should be described.

PHS 398 Form Page 3

Do not use Form Page 3 of the PHS 398; a more comprehensive
Table of Contents (TOC) is needed for this Center. Bearing in mind that the
application may be scientifically reviewed in sections based upon the proposed
structure of the HMP Collaborative Center, prepare a detailed TOC that will
enable reviewers to readily locate specific information pertinent to the
overall application as well as to any proposed Components of the Center.
Applicants must define a clear structure for the Center to aid in the review
and evaluation of the application. These Components may include
administrative, data coordinating, computational/informatics/statistical cores,
clinical sites, and/or laboratories (genomics, proteomics, metabolomics, etc.).
Further, each Component should be identified by name and responsible Component
Director. The page location of the overall budget should be indicated in the
TOC.

PHS 398 Form Pages 4-5

The Center budget should include the overall budget as well
as any details about the budget for the Components. Budget justifications
should be included. Major equipment costs will be allowed, if well justified.

Biographical Sketch Format Page

Biographical sketches of all personnel for all Components of
the Center should be included with the PD/PI first, followed by those of other
key personnel in alphabetical order.

Resources Format Page

For the Center, resources may include laboratory facilities,
equipment, and services. Depending of the proposed structure, describe in
detail the resource(s) that will part of each Component, and how it will add to
the Center.

Research Plan

All instructions in the PHS 398 Application Guide must be
followed, with the following additional instructions:

Specific
Aims

The Specific Aims should describe the overall goals
and structure of the HMP Collaborative Center.

Research
Strategy

The organization suggested below is optional and the
applicant is free to use an alternative presentation but, in so doing, must address
all of the issues raised below.

Background
and Preliminary Data. This section should include the
following:

General
introduction and justification. Applicants should present information about
past work related to the goals of this FOA. If the applicant has participated
as part of a collaborative research group, efforts to facilitate the success of
that larger group should be described.

Progress
Report. Applicants should describe their track record in studying the system
proposed and in utilizing the proposed methodologies. The application should
provide detailed information about throughput, quality, and cost for past
performance. If large-scale, high throughput technologies are proposed, then a
concise description of past experience with these technologies is required. The
application should describe the experience of the applicant and/or the
collaborators from the different Components with the proposed tools or in tool
development relevant to the data types to be analyzed. The description should also
include past experience in the approaches proposed for the incorporation of
different data types into a combined data set.

Rationale. The rationale for the choice of the human body site microbiome
to be studied with respect to the proposed disease or health state must be
addressed. In addition, the following areas should be addressed:

Describe
the biological system in which the relationship between the microbiome and
health/disease will be studied.

Justify
which features of the proposed specific disease or health state make it of
general use and interest to the broad research community for the study of the
microbiome and disease or health.

Describe
clearly the health or disease state and phenotypes to be examined, why the
cohort was chosen, and the rationale for the primary host phenotype(s) that
were used as the criteria for selection of the clinical biospecimen donors from
the cohort.

Justify
why additional microbiome data beyond microbial taxonomic composition are
needed in order to expand our understanding of the microbiome’s role in the
specific disease or health state under study.

Justify
what types of microbiome functional data will be collected, why these data need
to be collected for the health or disease condition under study, what methods
are proposed for collecting these data and why these methods were chosen for
the study.

The rationale for the approach used for incorporating
the different data types into one combined dataset for access and use by the
broader community must be addressed. In addition, the following areas should be
addressed:

Describe
the interface which will be adopted or developed to incorporate or link the
different data types and whether the data will be archived in different
databases or in one database.

If in
different databases, describe how the data will be incorporated into a
framework which will allow the community to query the data across the different
databases.

Describe
the interface which will be adopted or developed to incorporate or link the
microbiome data types with the human clinical phenotype, the human subject
sequence data or any other restricted data in dbGaP or other controlled access
database.

Describe
the type of derived data planned for each of the data types which will be the
data that is used for the combined dataset.

Describe
how the combined dataset will allow each of the data types to be queried
independently and how the combined dataset will be queried.

Any
results from an analysis which includes the controlled access data retain their
controlled access status. Describe what provisions will be made for results
which emerge from an analysis that includes controlled access data to be
archived in a controlled access database(s).

Describe
the existing IT infrastructure or tracking technologies that will be used to
create the combined dataset.

Describe
the proposed proof-of-principle test that will be used to evaluate the
useability of the combined dataset and whether it can be queried by the
broader community to address health or disease related hypotheses.

Describe
the database(s) where the data will be deposited and how the database will
provide controlled access and what procedure will be adopted or developed to
allow only qualified researchers from the broader community to request and gain
access to the controlled access data.

Overall
Center Structure, Governance and Management. The applicant can
select any type of Center structure that will best address the goals of the
FOA. Regardless of the proposed structure, the applicant must present a clear
organization of the different Components and a rationale for this structure.
There should also be inclusion of clear governance and management strategies.
The Center may include members from more than one institution. As these are
cooperative agreements, the governance and management of these Centers are
discussed below in the Cooperative Agreements section under Terms and
Conditions of the award. In particular, the following should be addressed:

Address
the bioinformatics and data management and data sharing strategies as part of
the organizational structure.

Sample
Choice and Collection. Applicants should propose to collect a
carefully defined set of clinical biospecimens, and phenotype data, from one or
more body sites, along with additional host tissues or biofluids, as
appropriate and well-justified in the application. Particular attention should
be given to sample collection protocols which support analysis of microbiome
properties. In addition, the application should fully address:

The
number of donors needed based on previous microbiome studies, if this
information is available.

The
primary phenotypes that form the basis for any power analyses and sample size
calculations. Other phenotypes and outcomes should also be described.

The
inclusion and exclusion criteria for the subjects in the cohort.

The
Standard Operating Procedures (SOPs) for sample collection from the designated
body region(s) and sites must be described, including a design for collection
of metadata (e.g., host characteristics, relevant environmental measurements),
and a plan to ensure correct sample tracking, storage and management. The
application must set out clear sampling plans with a timetable for
implementation for the plan.

Sample
Analyses and Data Production. Applicants can choose to use any
of the appropriate current robust technologies to collect microbiome taxonomic
composition data and a minimum of three of the four microbiome 'omic data
types, namely metagenomics, metatranscriptomics, metaproteomics and
metabolomics. In addition, because some of the methodologies can simultaneously
yield a combination of both microbiome and host data, specific host genomic and
host functional (transcriptome, proteome and metabolome or other) data may also
be generated and added to the combined data set, if well justified in the
application. If included, these human subject data should be stored in
controlled access databases. The application should address the following
areas:

How the
chosen technologies will be used to create data sets of sufficient quality and
depth to allow analysis aimed at studying how changes in functional properties
of the microbiome correlate to changes in human health or disease.

The
choice of approaches and analyses for microbiome taxonomic characterization,
transcriptomics, proteomics and metabolomics must be justified and the methods
well described.

Current
technical capabilities for each approach proposed and the quality of the data,
the amount of data that can be anticipated from each type of sample and the
current throughput capabilities of the technology in the applicants’
laboratories.

Preliminary
data for each methodology proposed should be included in the application.
Animal model data will be permitted for this preliminary data.

A
demonstration of the ability, through computational or analytical approaches,
to distinguish between host and microbiome contributions to the properties
being assayed in the tissue(s) or biofluids under study.

Several
different techniques may be proposed for each microbiome data type to be
generated but must be justified and well-described and with discussion of
effect size, presentation of power calculations (where appropriate and
available), quality control measures, and projected cost per sample for each
technique. These calculations and estimates should be based on prior
experience, preferably with a clinical biospecimen or animal model specimen for
microbiome study, and projections of throughput expectations.

Costs for
processing of each data type should be described and provided separately from
the cost for each assay type. The expected throughput for each methodology
should be well described.

Potential
bottlenecks or other anticipated problems and proposed solutions should be well
addressed.

Describe
a baseline quality standard. A description of how quality will be measured must
be given for all methodologies. This description should include how the quality
standard was developed and how quality will be measured during the project.

Strategies
to organize and standardize the microbiome data and the host clinical phenotype
data so that a combined HMP test dataset(s) can be produced that is easily
useable by the community should be addressed.

For each
methodology, the overall projected cost and throughput proposed for data
production in each year of requested funding should be included. The
description given above in the “progress report” (described below under the
Background and Preliminary Data section) may be used to project cost, quality
and throughput of the data produced by the proposed methodologies. Timelines
and quantitative milestones should be given where appropriate, especially for
throughput, cost and quality, of proposed methodologies.

Data
Processing, Organization and Release. The application must
describe strategies to utilize existing tools to process and organize the
derived microbiome and phenotype data types into a combined dataset suitable
for analysis by the broader community and if human subject data are included,
available to only qualified researchers through a controlled access database
for subsequent analysis. The application must also address:

The
proposed ‘data snapshot’ or data milestone. The application should justify the
stage at which an early data milestone will occur and what results can be
expected from a combination of the different data into this early dataset.

The
informatics that will be used to support the data production and processing,
including routine IT/systems administration, LIMS, quality assessment, etc.

Any
bioinformatic tool improvement needed for processing and combining the dataset.
Because of the short timeline of this initiative, development of new tools is
not included in this FOA, but improvement of existing tools may be feasible and
support for tools improvement may be included in the application. If
applicants choose to improve existing tools, tool improvement should be
thoroughly described and justified. Descriptions of what tools will be used
should also include the applicants’ experiences in using them, preferably with
microbiome data. Applicants should also discuss the strengths and weaknesses
of the tools in the context of the proposed project.

The
bioinformatics and computational approaches that will be used to carry out a
proof-of-principle test of both an early set of the combined data and of the
final combined dataset to evaluate the useability of the dataset by the broader
community to address microbiome and health related hypotheses.

The
existing tools that will be used or improved for these proof-of-principle tests.

As
needed, the plans to engage external members of the community in this
proof-of-principle analysis.

The proposed data release plans and tools should be
fully described. All data generated through this initiative will be released
rapidly and, if it includes human subject data, into a controlled access
database(s), available to qualified researchers in the broader community. A
data release policy for the data from each of the methodologies being used
should be addressed. For this application, the NIAID data release policy
should be followed (http://www.niaid.nih.gov/LabsAndResources/resources/dmid/gsc/Pages/data.aspx).
These plans will be reviewed by NIH staff, and agreed upon with the applicant
before the application is funded.

Milestones. The application must include an estimate of the timeline for
initiating and completing the project to include but not be limited to:

Consenting
and/or reconsenting (if necessary) of human subjects and collection of the
clinical biospecimens and clinical phenotype data for broad data sharing
through a controlled access database(s) to qualified researchers;

Generation
of the multiple 'omic data types from the microbiome and from the host;

Data
processing and incorporation into a combined dataset;

Deposition
of data into appropriate archives, to also include deposition into controlled
access databases of human subject phenotype, sequence and other human subject
data;

An early
proof-of-principle test of an early combined dataset and a proof-of-principle
test of the final combined dataset.

The Components of the HMP Collaborative Center(s)
will need to be closely coordinated to accomplish the program goals within
three years. The timelines should reflect this close coordination across the
Components. This is a Cooperative Agreement, and so the final timeline will be negotiated
at the time of the award.

Human
Subjects

Identification
of an appropriate cohort. Applicants must describe an existing
or readily accessible set or collection of donors/samples from a human cohort
study. The subjects providing the samples must be/have been consented in a
manner consistent with NHGRI policies and follow NIH guidelines for genomics
research, which are also applicable to microbiome research (http://www.genome.gov/27026588), so
that the samples can be utilized in the analysis of microbiome genomic and
functional properties. If the subjects are not already consented for broad
sharing of microbiome metagenomic and functional data which includes
deposition of data in open access databases, the applicant must detail the
reconsent process and the timeline for completing it within the first year of
the grant. The consents should note the remote but potential risk to privacy
of sharing their microbiome data in open access databases. The applicants
should also address how they plan to minimize risks to the subjects' privacy in
the Protection to Human Subjects section of the application. Because of the
3-year period of this initiative, utilization of an existing broadly consented
cohort which allows for broad sharing of the microbiome and host data is
strongly encouraged. Broad sharing is desired in order to maximize community
use of the combined dataset.

Resource Sharing Plan

Individuals are required to comply with the
instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model
Organisms, and Genome Wide Association Studies (GWAS)) as provided in the PHS 398
Application Guide, with the following modifications:

1. The application for a HMP funded project must
include a plan for sharing research data. The HMP strongly endorses rapid
release of HMP-related data and materials. Applicants should refer to specific
NIAID policy on data release (http://www.niaid.nih.gov/LabsAndResources/resources/dmid/gsc/Pages/data.aspx)
for submission of all data types. Because the purpose of this FOA is to fund
the generation of an exploratory combined dataset of microbiome multi 'omic
data and corresponding host phenotype data, the utility of such data to the
community is largely dependent on how quickly it can be deposited into public
databases which include controlled access for human subject data or appropriate
websites which include controlled access for the human subject data. The NIH
considers this FOA to be funding community resource projects as discussed in
the report “Sharing Data From Large-Scale Biological Research Projects - 2003:
A System of Tripartite Responsibility” available at http://www.genome.gov/10506376, which
deals primarily with sequence data but is applicable in principle to all data
types. The general NIH data sharing policy is available at http://grants.nih.gov/grants/policy/data_sharing.
All investigators responding to this funding opportunity should include a
description of how research data will be shared and, if human subject data, for
data archived in a controlled access database(s).

2. Responses to this FOA should propose a plan for
data release as quality of the data release plan will be a criterion in the
review of the application. Appropriate data release plans will be made a
condition of the awards made as a result of this FOA. In some cases, public
databases may not be available for some of the data types generated in this
project. In these cases, the applicant should describe the data release plan
that may make use of appropriate controlled access websites or describe the
creation of an appropriate controlled access website which can archive the data
and can make the data available to the larger research community via a
procedure for qualified researchers to apply for and gain access to the data.
Each of the following items should be discussed separately:

Release
of cohort subject phenotype and human sequence data to a controlled access data
site specified by the NIH;

Release
of the other types of data used to characterize the functional properties of
the microbiome in the system being proposed for the study to include some
combination of the microbiome taxonomic composition with the microbiome
metagenome, transcriptome, proteome or metabolome;

Release
of clinical metadata associated with the microbiome multi 'omic data and the
host clinical phenotype data to a controlled access site; and

Release
of analyses performed by the awardee. If these analyses include controlled
access data then how results of these analyses will be archived in controlled
access databases.

3. All applicants must include a plan for sharing
research data and reagents including clones and organisms in their application.
All investigators responding to this funding opportunity should include a
description of how final research data, including the derived combined test
data set, will be shared with the broader research community, if needed,
through the use of controlled access databases.

NIH staff will review the Data Sharing and Release
Plan prior to making the award. The Data Sharing and Release Plan will also be
a part of the review of the application.

Appendix

Do not use the Appendix to circumvent page limits. Follow
all instructions for the Appendix (please note all format requirements) as
described in the PHS 398 Application Guide.

Applications must be received on or before the due dates in Part I. Overview Information. If an
application is received after that date, it will not be reviewed.

Upon receipt, applications will be evaluated for
completeness by the Center for Scientific Review and responsiveness by components of participating organizations,
NIH. Applications that are incomplete and/or nonresponsive will not be
reviewed.

Post Submission Materials

Applicants are required to follow the instructions for
post-submission materials, as described in NOT-OD-10-115.

Section V. Application Review Information

1.
Criteria

Only the review criteria described below will be considered
in the review process. As part of the NIH mission,
all applications submitted to the NIH in support of biomedical and behavioral
research are evaluated for scientific and technical merit through the NIH peer
review system.

Overall Impact - Overall

Reviewers will provide an overall impact score to reflect
their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of
the following review criteria and additional review criteria (as applicable for
the project proposed).

Scored Review Criteria - Overall

Reviewers will consider each of the review criteria below in
the determination of scientific merit, and give a separate score for each. An
application does not need to be strong in all categories to be judged likely to
have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Significance

Does the project address an important problem or a
critical barrier to progress in the field? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical
practice be improved? How will successful completion of the aims change the
concepts, methods, technologies, treatments, services, or preventative
interventions that drive this field? Is there a high likelihood that the
proposed effort can produce a novel and useful set of microbiome taxonomic,
metagenomic and/or functional property data? Is there a high likelihood that
the broader community will be able to use this combined dataset for analyses?
Is there a high likelihood that analysis of these data will provide important
information pertinent to understanding the role of the microbiome to human
health and disease?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other
researchers well suited to the project? If Early Stage Investigators or New
Investigators, or in the early stages of independent careers, do they have
appropriate experience and training? If established, have they demonstrated an
ongoing record of accomplishments that have advanced their field(s)? If the
project is collaborative or multi-PD/PI, do the investigators have
complementary and integrated expertise; are their leadership approach,
governance and organizational structure appropriate for the project? Do the members of the investigative team show evidence of previous successful
collaborations?

If new collaborations are proposed, are the plans
adequate to ensure a productive collaboration? Is the commitment of all
individuals appropriate? Do the research team members have proven track records
in generating, analyzing and releasing high throughput data? Do the members of
the collaboration show demonstrated ability to work together in consortia?

Innovation

Does the application challenge and seek to shift
current research or clinical practice paradigms by utilizing novel theoretical
concepts, approaches or methodologies, instrumentation, or interventions? Are
the concepts, approaches or methodologies, instrumentation, or interventions
novel to one field of research or novel in a broad sense? Is a refinement,
improvement, or new application of theoretical concepts, approaches or
methodologies, instrumentation, or interventions proposed?

Approach

Are the overall strategy, methodology, and analyses
well-reasoned and appropriate to accomplish the specific aims of the project? Are potential problems, alternative strategies, and benchmarks for success presented?
If the project is in the early stages of development, will the strategy
establish feasibility and will particularly risky aspects be managed?

If the project involves clinical research, are the plans for 1) protection of
human subjects from research risks, and 2) inclusion of minorities and members
of both sexes/genders, as well as the inclusion of children, justified in terms
of the scientific goals and research strategy proposed?

Does the applicant include language in the consent that informs
the subjects of the remote but potential risk to privacy of data which is in
open access?

Has the applicant adequately justified the choice for the disease
or health state being studied? Has the applicant provided a rationale for the
cohort, the primary host phenotypes used for the selection of clinical
biospecimens, and the choice of microbiome and body region(s) with respect to
the proposed health or diseased states? Is there a clear rationale for why
additional microbiome data beyond taxonomic composition are needed, as well as
the choice of data and proposed methods?

Is the proposed Center structure appropriate? Are the governance,
management and succession plans well described and appropriate? Are
communication strategies clear, including well described research network
consortium meetings?

Will the donor recruitment or biospecimen sampling plan presented
provide the needed resource for this study? Are the number of samples
appropriate, given the primary host phenotypes and data to be collected? Are
the inclusion and exclusion criteria, sample acquisition plans, consenting or
reconsenting and standard operating procedures for processing of the
biospecimens for the proposed assays well described and appropriate? Does the
applicant plan to carry out enrollment of a new cohort or consent a new cohort?

Are the proposed sample analysis methodologies robust,
cost-effective and state of the art? Has data quality been adequately
addressed? Does the applicant have the infrastructure/laboratory information
management needed for the proposed program?

Are the informatics to be used to support data production,
processing and incorporation into a combined dataset well described and
appropriate? Have the approaches proposed to identify the data derivatives to
go into the combined dataset well described and appropriate? Are there appropriate
approaches to distinguish between host and microbiome contributions? Are there
well described power analyses and statistical strategies?

Has the applicant identified an appropriate potential "data
snapshot" (i.e., data milestone time point) and described adequate
proof-of-principle test plans? Are the plans to include external input
adequate?

Does the applicant have adequate plans for a proof-of-principle
test of the final exploratory data set to be generated? Does he/she have
adequate experience in utilizing the proposed analysis tools or in improving
tools? Does the applicant have plans to engage the broader community in the
proof-of-principle test of the useability of the dataset?

Does the applicant have adequate plans for combining the data set
and for release of the combined dataset to the broader community?

Are the plans and policies adequate for release of all types of
data generated through this project, including metadata? If human subject data,
will the data be de-identified prior to deposition in a controlled access
site(s)? If human subject data, are plans and procedures in place to release
the data types into a controlled access site(s)? Are there plans and procedures
in place for only qualified researchers to apply for and gain access to the
data in the controlled access site? Is there evidence that the systems are in
place to support rapid data release? Are there adequate plans for release or
distribution of other resources, software, or technologies developed under this
award? Has the application fully addressed the release of cohort subject and
sequence data, metadata, any other data, analyses, clones and reagents?

Does the applicant include detailed milestones and timelines? Are
the proposed timelines and milestones appropriate for the various aspects of
the project including sample generation, data generation, incorporation into a
combined dataset, and release?

Environment

Will the scientific environment in which the work
will be done contribute to the probability of success? Are the institutional
support, equipment and other physical resources available to the investigators
adequate for the project proposed? Will the project benefit from unique
features of the scientific environment, subject populations, or collaborative
arrangements?

Additional Review Criteria - Overall

As applicable for the project proposed, reviewers will
evaluate the following additional items while determining scientific and
technical merit, and in providing an overall impact score, but will not give
separate scores for these items.

Protections for Human Subjects

For research that involves human subjects but does
not involve one of the six categories of research that are exempt under 45 CFR
Part 46, the committee will evaluate the justification for involvement of human
subjects and the proposed protections from research risk relating to their
participation according to the following five review criteria: 1) risk to
subjects, 2) adequacy of protection against risks, 3) potential benefits to the
subjects and others, 4) importance of the knowledge to be gained, and 5) data
and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or
more of the six categories of research that are exempt under 45 CFR Part 46,
the committee will evaluate: 1) the justification for the exemption, 2) human
subjects involvement and characteristics, and 3) sources of materials. For
additional information on review of the Human Subjects section, please refer to
the Human
Subjects Protection and Inclusion Guidelines.

Inclusion of Women, Minorities, and
Children

When the proposed project involves clinical research, the committee will evaluate the proposed plans for inclusion of
minorities and members of both genders, as well as the inclusion of children. For
additional information on review of the Inclusion section, please refer to the Human Subjects
Protection and Inclusion Guidelines.

Vertebrate Animals

The committee will evaluate the involvement of live
vertebrate animals as part of the scientific assessment according to the
following five points: 1) proposed use of the animals, and species, strains,
ages, sex, and numbers to be used; 2) justifications for the use of animals and
for the appropriateness of the species and numbers proposed; 3) adequacy of
veterinary care; 4) procedures for limiting discomfort, distress, pain and
injury to that which is unavoidable in the conduct of scientifically sound
research including the use of analgesic, anesthetic, and tranquilizing drugs
and/or comfortable restraining devices; and 5) methods of euthanasia and reason
for selection if not consistent with the AVMA Guidelines on Euthanasia. For
additional information on review of the Vertebrate Animals section, please
refer to the Worksheet
for Review of the Vertebrate Animal Section.

Biohazards

Reviewers will assess whether materials or procedures
proposed are potentially hazardous to research personnel and/or the
environment, and if needed, determine whether adequate protection is proposed.

Resubmissions

Not Applicable

Renewals

Not Applicable

Revisions

Not Applicable

Additional Review Considerations - Overall

As applicable for the project proposed, reviewers will
consider each of the following items, but will not give scores for these items,
and should not consider them in providing an overall impact score.

Applications from Foreign
Organizations

Not Applicable

Select Agent Research

Reviewers will assess the information provided in
this section of the application, including 1) the Select Agent(s) to be used in
the proposed research, 2) the registration status of all entities where Select
Agent(s) will be used, 3) the procedures that will be used to monitor
possession use and transfer of Select Agent(s), and 4) plans for appropriate
biosafety, biocontainment, and security of the Select Agent(s).

Reviewers will consider whether the budget and the
requested period of support are fully justified and reasonable in relation to
the proposed research.

2. Review and Selection
Process

Applications will be evaluated for scientific and technical
merit by (an) appropriate Scientific Review Group(s), convened by the National Institute of Dental and Craniofacial Research in accordance with NIH peer
review policy and procedures, using the stated review
criteria. Assignment to a Scientific Review Group will be shown in the eRA
Commons.

As part of the scientific peer review, all applications:

May undergo a selection process in which only those applications
deemed to have the highest scientific and technical merit (generally the top
half of applications under review) will be discussed and assigned an overall
impact score.

Will receive a written critique.

Appeals of initial peer review will not be accepted for applications submitted response
to this FOA.

Applications will be assigned to the appropriate NIH Institute or Center and will compete for available funds with all
other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of
review by the NIDCR Council. The following will be considered in making funding
decisions:

Scientific and technical merit of the proposed project as
determined by scientific peer review.

Availability of funds.

Relevance of the proposed project to program priorities.

3. Anticipated Announcement
and Award Dates

After the peer review of the application is completed, the
PD/PI will be able to access his or her Summary Statement (written critique)
via the eRA
Commons.

If the application is under consideration for funding, NIH
will request "just-in-time" information from the applicant as
described in the NIH Grants
Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided
to the applicant organization for successful applications. The NoA signed by
the grants management officer is the authorizing document and will be sent via
email to the grantee’s business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection
of an application for award is not an authorization to begin performance. Any
costs incurred before receipt of the NoA are at the recipient's risk. These
costs may be reimbursed only to the extent considered allowable pre-award costs.

The following special terms of award are in addition to, and
not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB)
administrative guidelines, U.S. Department of Health and Human Services (DHHS)
grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is
applicable when State and local Governments are eligible to apply), and other
HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the
cooperative agreement, an "assistance" mechanism (rather than an
"acquisition" mechanism), in which substantial NIH programmatic
involvement with the awardees is anticipated during the performance of the
activities. Under the cooperative agreement, the NIH purpose is to support and
stimulate the recipients' activities by involvement in and otherwise working
jointly with the award recipients in a partnership role; it is not to assume
direction, prime responsibility, or a dominant role in the activities.
Consistent with this concept, the dominant role and prime responsibility
resides with the awardees for the project as a whole, although specific tasks
and activities may be shared among the awardees and the NIH as defined below.

The
PD(s)/PI(s) will have the primary responsibility for:

The Program Director/Principal Investigator (PD/PI) will
have the primary responsibility for defining the details for the HMP
Exploratory Microbiome Study within the guidelines of this FOA and for
performing the scientific activities. The PD/PI will agree to accept close
coordination, cooperation, and participation of NIH HMP Program staff in those
aspects of scientific and technical management of the project as described
under "NIH Program Staff Responsibilities."

Provide goals for production, quality, and cost of data to be
generated to the NIH HMP staff as requested (usually at the outset of the award
and annually thereafter, but also at other times as requested by NIH HMP
staff);

Ensure that the data produced meets the quality standards and
costs agreed upon at the time of award or any improved quality standards and
costs negotiated during the award period;

Ensure that the data of all types (such as clinical data, reads,
assemblies, metadata, expression data, mass spectra, proteomic data and
metabolomic data, as both raw data and derived data) are deposited in the
appropriate controlled access public database (e.g., SRA, GEO or other, as
specified by NIH HMP staff) or, if needed, at appropriate controlled access
websites (as agreed to at the time of the award), that resources developed as
part of this project are made publicly available according to NHGRI and NIAID
policies, and that results are published in a timely manner;

Adhere to the NIH NHGRI and NIAID policies regarding intellectual
property, data release and other policies that might be established during the
course of this activity;

Submit quarterly progress reports;

Accept and implement any other common guidelines and procedures
developed for the HMP program;

Actively work to support and promote the Human Microbiome Project
Research Network Consortium (HMP Consortium) goals and objectives;

Organize/run the HMP Consortium meetings, to occur annually as
face-to-face meetings and as virtual meetings and conference calls on a more
frequent basis. The purpose of these meetings will include, but not be limited
to, discussing 1) sample preparation and acquisition, 2) analytical procedures
for the different data types, 3) data harmonization and standards for the
different data types, 4) establishing the data milestones, 5) data structure
for and creation of the combined test dataset, 6) computational challenges in
testing the useability of the combined dataset, 7) identification or
development of appropriate databases for archiving the primary and derived data
produced under the FOA and 8) planning for publications. Best practices are
expected to emerge from these discussions and will be shared through Center
websites and in Consortium publications.

Awardees will retain custody of and have primary rights to
the data and software developed under these awards, subject to Government
rights of access consistent with current DHHS, PHS, and NIH policies.

NIH
staff have substantial programmatic involvement that is above and beyond the
normal stewardship role in awards, as described below:

NIH Project Scientists will have substantial programmatic
involvement that is above and beyond the normal stewardship role in awards, as
described below. NIH HMP Project Scientists will have substantial
scientific/programmatic involvement during the conduct of this activity through
technical assistance, advice and coordination. However, the role of NIH
HMP Project Scientists will be to facilitate and not to direct the activities.
It is anticipated that decisions in all activities will be reached by consensus
of the HMP Consortium and NIH HMP Project staff will be given the opportunity
to offer input to this process.

The Project Scientists will:

Participate in the group process of setting research priorities,
deciding optimal research approaches and protocol designs, and contributing to
the adjustment of research protocols or approaches as warranted. The Project
Scientists will assist and facilitate the group process and not direct it;

Negotiate throughput, quality, cost goals, and sampling needs
with the awardees as necessary;

Periodically report progress to the Directors of relevant NIH
Institutes and Offices;

Provide advice in the management and technical performance of the
investigation;

Assist in promoting the availability of the human microbiome data
and related resources developed in the course of this project to the scientific
community at large;

Participate in data analyses, interpretations, and where
warranted, co-authorship of the publication of results of studies conducted
through the HMP Consortium;

Assist awardees in the development, if needed, of policies for
dealing with situations that require coordinated action;

Retain the option to recommend the withholding or reduction of
support from any cooperative agreement that substantially fails to achieve its
goals according to the milestones agreed to at the time of award, fails to
maintain state-of-the-art capabilities, or fails to comply with the Terms and
Conditions of the award.

Additionally, an NIH agency program official or IC program
director will be responsible for the normal scientific and programmatic
stewardship of the award and will be named in the award notice. The assigned
program director may also serve as the NIH Project Scientist.

Areas
of Joint Responsibility include:

A Steering Committee will serve as the main governing board
of the HMP Consortium. The Steering Committee membership will include NIH HMP
Project Scientists and the PIs of each awarded cooperative agreement. The
PI of each HMP Collaborative Center (or designee) will have one vote on the
Steering Committee. The Project Scientists may vote, but the total NIH votes
will count as a maximum of one-third of the total number of votes. The
Steering Committee Chair will rotate on an annual basis and will not be an NIH
staff member. Additional members may be added by action of the Steering
Committee. Other government staff may attend the Steering Committee meetings,
if their expertise is required for specific discussions. The Steering Committee
will:

Discuss progress in meeting the goals of the FOA.

Agree which external community members should be formal members
of the HMP Consortium. The HMP Consortium will consist of the funded grantees
of awards made under this RFA as well as external members of the community, as
appropriate. In some cases these members will not be funded through the HMP
program but may bring specific expertise to the HMP Consortium. Membership
considerations include contributions to the data processing or analysis of the
combined test dataset or other contributions as needed in the HMP Consortium.
New members will be announced at the next HMP Consortium meeting or via email
to the HMP Consortium and each new member will be provided with a copy of the
Consortium guidelines.

Develop recommendations for uniform procedures and policies
necessary to meet the goals of the HMP Consortium, for example for data quality
measures and assessment, conventions for data deposition, or measuring costs
and throughput.

Serve as a venue for coordination on the improvement of human
microbiome scientific methods, for example by disseminating best practices and
collectively evaluating new procedures, resources, and technologies.

Schedule the time for, and prepare concise (3 to 4 pages)
summaries of the Steering Committee meetings, which will be delivered to
members of the group within 30 days after each meeting.

Awardee members of the Steering Committee will be required to
accept and implement policies approved by the Steering Committee.

External
Scientific Consultants

The External Scientific Consultants (ESC) will be
responsible for reviewing and evaluating the progress of the members of the
Human Microbiome Project Research Network Consortium toward meeting their
individual and collective goals. The ESC will provide recommendations to the
Directors of NHGRI, NIAID, NIDCR, NIDDK and the NIH Office of Strategic
Coordination about continued support of the components of the HMP program. The
panel will be composed of three senior scientists with relevant expertise who
are not P.I.s of a cooperative agreement involved in the HMP Consortium. The membership
of the External Scientific Consultants may be enlarged permanently, or on an ad
hoc basis, as needed.

The External Scientific Consultants will meet at least once
a year with the HMP Consortium. During part of this meeting, there will be a
joint meeting with the Steering Committee to allow the ESC members to interact
directly with the awardees. Annually, the ESC will make recommendations
regarding progress of the HMP Consortium and present advice about changes, if
any, which may be necessary in the HMP Consortium or the program to the
Directors of NHGRI, NIAID, NIDCR, NIDDK and NIH Office of Strategic
Coordination.

Dispute
Resolution:

Any disagreements that may arise in scientific or
programmatic matters (within the scope of the award) between award recipients
and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel will
be convened. The Panel will have three members: a designee of the Steering
Committee chosen without NIH staff voting, one NIH designee, and a third
designee with expertise in the relevant area who is chosen by the other two.
This special dispute resolution procedure does not alter the awardee's right to
appeal an adverse action that is otherwise appealable in accordance with PHS
regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

3. Reporting

When multiple years are involved, awardees will be required
to submit the Non-Competing Continuation Grant Progress Report (PHS 2590 or RPPR)
annually and financial statements as required in the NIH
Grants Policy Statement.

Awardees will also be required to submit periodic
(quarterly) progress reports in a standard format, as agreed upon by the
Steering Committee and the ESC. As part of good program management, the NIH may
request information essential to an assessment of the effectiveness of this
Program. Accordingly, recipients are hereby notified that grantees may be asked
to provide information for program evaluation purposes, both locally and at the
national level.

The NIH will evaluate this program. Each awardee will be
required to define concrete and quantifiable project-specific quarterly and 1
year milestones for the U54. Prior to funding the application, program staff
will negotiate the milestones with the applicant. The negotiated milestones
will become a condition of the award, including appropriate language to
recognize that the project includes research the outcomes of which are
unpredictable. Each awardee will be required to update these milestones
annually at the anniversary date. In addition, each awardee is expected to
provide additional information as required to assist the program evaluation.
In accord with the procedures described above, NIH may withhold or reduce funds
for a project that substantially fails to meet its milestones or to maintain the
state of the art.

A final progress report, invention statement, and the
expenditure data portion of the Federal Financial Report are required for
closeout of an award, as described in the NIH Grants
Policy Statement.

The Federal Funding Accountability and Transparency Act of
2006 (Transparency Act), includes a requirement for awardees of Federal grants
to report information about first-tier subawards and executive compensation under
Federal assistance awards issued in FY2011 or later. All awardees of
applicable NIH grants and cooperative agreements are required to report to
the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants
Policy Statement for additional information on this reporting
requirement.

Section VII. Agency Contacts

We encourage inquiries concerning this funding opportunity
and welcome the opportunity to answer questions from potential applicants.

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and
under Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92.